Buccal, polar and non-polar spray or capsule

ABSTRACT

Buccal aerosol sprays or capsule using polar and non-polar solvent have now been developed which provide biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect. The buccal polar compositions of the invention comprises formulation I: aqueous polar solvent 30-99.89%, active compound 0.001-60%, optionally containing flavoring agent 0.1-10%. Propellant 2-10%. The non polar composition of the invention comprises formulation II: non-polar solvent 20-85%, active compound 0.005-50%, and optionally flavoring agent 0.1-10% and propellant 50-80%.

RELATED APPLICATIONS

This application is a divisional of application Ser. No. 09/537,118,filed Mar. 29, 2000, which is a continuation-in-part of PCT applicationPCT/US97/17899 filed Oct. 1, 1997, the content of which is expresslyincorporated herein by reference thereto.

BACKGROUND OF THE INVENTION

It is known that certain biologically active compounds are betterabsorbed through the oral mucosa than through other routes ofadministration, such as through the stomach or intestine. However,formulations suitable for such administration by these latter routespresent their own problems. For example, the biologically activecompound must be compatible with the other components of the compositionsuch as propellants, solvents, etc. Many such formulations have beenproposed. For example, U.S. Pat. No. 4,689,233, Dvorsky et al.,describes a soft gelatin capsule for the administration of theanti-coronary drug nifedipine dissolved in a mixture of polyetheralcohols. U.S. Pat. No. 4,755,389, Jones et al., describes a hardgelatin chewable capsule containing nifedipine. A chewable gelatincapsule containing a solution or dispersion of a drug is described inU.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919,919, Aouda etal, and U.S. Pat. No. 5,370,862, Klokkers-Bethke, describe anitroglycerin spray for administration to the oral mucosa comprisingnitroglycerin, ethanol, and other components. An orally administeredpump spray is described by Cholcha in U.S. Pat. No. 5,186,925. Aerosolcompositions containing a hydrocarbon propellant and a drug foradministration to a mucosal surface are described in U.K. 2,082,457, Su,U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat. No. 5,011,678, Wang etal., and by Parnell in U.S. Pat. No. 5,128,132. It should be noted thatthese references discuss bioavailability of solutions by inhalationrather than through the membranes to which they are administered.

SUMMARY OF THE INVENTION

A buccal aerosol spray or soft bite gelatin capsule using a polar ornon-polar solvent has now been developed which provides biologicallyactive compounds for rapid absorption through the oral mucosa, resultingin fast onset of effect.

The buccal aerosol spray compositions of the present invention, fortransmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable non-polar solvent comprise inweight % of total composition: pharmaceutically acceptable propellant5-80%, non-polar solvent 20-85%, active compound 0.05-50%, suitablyadditionally comprising, by weight of total composition a flavoringagent 0.01-10%. Preferably the composition comprises: propellant 10-85%,non-polar solvent 25-89.9%, active compound 0.01-40%, flavoring agent1-8%; most suitably propellant 20-70%, non-polar solvent 30-74.75%,active compound 0.25-35%, flavoring agent 2-7.5%.

The buccal polar aerosol spray compositions of the present invention,for transmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable polar solvent are alsoadministrable in aerosol form driven by a propellant. In this case thecomposition comprise in weight% of total composition: aqueous polarsolvent 10-99%, active compound 0.1-25%, suitably additionallycomprising, by weight of total composition a flavoring agent 0.05-10%and propellant: 2-10%. Preferably the composition comprises: polarsolvent 20-97 %, active compound 0.1-15%, flavoring agent 0.1-5% andpropellant: 3-5%; most suitably polar solvent 25-97%, active compound0.2-25%, flavoring agent 0.1-2.5% and propellant: 3-4%.

The buccal pump spray composition of the present invention fortransmucosal administration of a pharmacologically active compound wheresaid active compound is soluble in a pharmacologically acceptablenon-polar solvent said composition comprise in weight % of totalcomposition: non-polar solvent 30-99.69%, active compound 0.005-55%, andsuitably additionally, flavoring agent 0.1-10%.

The buccal polar pump spray compositions of the present invention, fortransmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable polar solvent comprising inweight % of total composition: aqueous polar solvent 30-99.69%, activecompound 0.001-60%, suitably additionally comprising, by weight of totalcomposition a flavoring agent 0.1-10%. Preferably the compositioncomprises: polar solvent 37-98.58%, active compound 0.005-55%, flavoringagent 0.5-8%; most suitably polar solvent 60.9-97.06%, active compound0.01-40%, flavoring agent 0.75-7.5%.

The soft bite gelatin capsules of the present invention for transmucosaladministration of a pharmacologically active compound, at leastpartially soluble in a pharmacologically acceptable non-polar solvent,having charged thereto a fill composition comprise in weight % of totalcomposition: non-polar solvent 4-99.99%, emulsifier 0-20%, activecompound 0.01-80%, provided that said fill composition contains lessthan 10% of water, suitably additionally comprising, by weight of thecomposition: flavoring agent 0.01-10%. Preferably, the soft bite gelatincapsule comprises: non-polar solvent 21.5-99.975%, emulsifier 0-15%,active compound 0.025-70%, flavoring agent 1-8%; most suitably:non-polar solvent 28.5-97.9%, emulsifier 0-10%, active compound0.1-65.0%, flavoring agent 2-6%.

The soft bite polar gelatin capsules of the present invention fortransmucosal administration of a pharmacologically active compound, atleast partially soluble in a pharmacologically acceptable polar solvent,having charged thereto a composition comprising in weight % of totalcomposition: polar solvent 25-99.89%, emulsifier 0-20%, active compound0.01-65%, provided that said composition contains less than 10% ofwater, suitably additionally comprising, by weight of the composition:flavoring agent 01-10%. Preferably, the soft bite gelatin capsulecomprises: polar solvent 37-99.95%, emulsifier 0-15%, active compound0.025-55%, flavoring agent 1-8%; most suitably: polar solvent44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring agent2-6%.

It is an object of the invention to coat the mucosal membranes eitherwith extremely fine droplets of spray containing the active compounds ora solution or paste thereof from bite capsules.

It is also an object of the invention to administer to the oral mucosaof a mammalian in need of same, preferably man, by spray or bitecapsule. a predetermined amount of a biologically active compound bythis method or from a soft gelatin bite capsule.

A further object is a sealed aerosol spray container containing acomposition of the non polar or polar aerosol spray formulation, and ametered valve suitable for releasing from said container a predeterminedamount of said composition.

As the propellant evaporates after activation of the aerosol valve, amist of fine droplets is formed which contains solvent and activecompound.

The propellant is a non-Freon material, preferably a C₃₋₈ hydrocarbon ofa linear or branched configuration. The propellant should besubstantially non-aqueous. The propellant produces a pressure in theaerosol container such that under expected normal usage it will producesufficient pressure to expel the solvent from the container when thevalve is activated but not excessive pressure such as to damage thecontainer or valve seals.

The non-polar solvent is a non-polar hydrocarbon, preferably a C₇₋₁₈hydrocarbon of a linear or branched configuration, fatty acid esters,and triglycerides, such as miglyol. The solvent must dissolve the activecompound and be miscible with the propellant, i.e., solvent andpropellant must form a single phase at 0-40° C. at a pressure range of1-3 atm.

The polar and non-polar aerosol spray compositions of the invention areintended to be administered from a sealed, pressurized container. Unlikea pump spray, which allows the entry of air into the container afterevery activation, the aerosol container of the invention is sealed atthe time of manufacture. The contents of the container are released byactivation of a metered valve, will does not allow entry of atmosphericgasses with each activation. Such containers are commercially available.

A further object is a pump spray container containing a composition ofthe pump spray formulation, and a metered valve suitable for releasingfrom said container a predetermined amount of said composition.

A further object is a soft gelatin bite capsule containing a compositionof as set forth above. The formulation may be in the form of a viscoussolution or paste containing the active compounds. Although solutionsare preferred, paste fills may also be used where the active compound isnot soluble or only partially soluble in the solvent of choice. Wherewater is used to form part of the paste composition, it should notexceed 10% thereof. (All percentages herein are by weight unlessotherwise indicated.)

The polar or non-polar solvent is chosen such that it is compatible withthe gelatin shell and the active compound. The solvent preferablydissolves the active compound. However, other components wherein theactive compound is not soluble or only slightly soluble may be used andwill form a paste fill.

Soft gelatin capsules are well known in the art. See, for example, U.S.Pat. No. 4,935,243, Borkan et al., for its teaching of such capsules.The capsules of the present invention are intended to be bitten into torelease the low viscosity solution or paste therein, which will thencoat the buccal mucosa with the active compounds. Typical capsules,which are swallowed whole or bitten and then swallowed, deliver theactive compounds the stomach, which results in significant lag timebefore maximum blood levels can be achieved or subject the compound to alarge first pass effect. Because of the enhanced absorption of thecompounds through the oral mucosa and no chance of a first pass effect,use of the bite capsules of the invention will eliminate much of the lagtime, resulting in hastened onset of biological effect. The shell of asoft gelatin capsule of the invention may comprise, for example:

Gelatin: 50-75%, glycerin 20-30%, colorants 0.5-1.5%, water 5-10%, andsorbitol 2-10%.

The active compound may include biologically active peptides, centralnervous system active amines, sulfonyl ureas, antibiotics, antifungals,anti-virals, sleep inducers, antiasthmatics, bronchial dilators,antiemetics, histamine H-2 receptor antagonists, barbiturates,prostaglandins and neutraceuticals.

The active compounds may also include antihistamines, alkaloids,hormones, benzodiazepines and narcotic analgesics. While not limitedthereto, these active compounds are particularly suitable for non-polarpump spray formulation and application.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a schematic diagram showing routes of absorption andprocessing of pharmacologically active substances in a mammalian system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred active compounds of the present invention are in anionized, salt form or as the free base of the pharmaceuticallyacceptable salts thereof (provided, for the aerosol or spraycompositions, they are soluble in the spray solvent). These compoundsare soluble in the non-polar solvents of the invention at usefulconcentrations or can be prepared as pastes at useful concentrations.These concentrations may be less than the standard accepted dose forthese compounds since there is enhanced absorption of the compoundsthrough the oral mucosa. This aspect of the invention is especiallyimportant when there is a large (40-99.99%) First pass effect.

As propellants for the non polar sprays, propane, N-butane, iso-butane,N-pentane, iso-pentane, and neo-pentane, and mixtures thereof may beused. N-butane and iso-butane, as single gases, are the preferredpropellants. It is permissible for the propellant to have a watercontent of no more than 0.2%, typically 0.1-0.2%. (All percentagesherein are by weight unless otherwise indicated.) It is also preferablethat the propellant be synthetically produced to minimize the presenceof contaminants which are harmful to the active compounds. Thesecontaminants include oxidizing agents, reducing agents, Lewis acids orbases, and water. The concentration of each of these should be less than0.1%, except that water may be as high as 0.2%.

Suitable non-polar solvents for the capsules and the non-polar spraysinclude (C₂-C₂₄) fatty acid C₂-C₆ esters, C₇-C₁₈ hydrocarbon, C₂-C₆alkanoyl esters, and the triglycerides of the corresponding acids. Whenthe capsule fill is a paste, other liquid components may be used insteadof the above low molecular weight solvents. These include soya oil, cornoil, other vegetable oils.

As solvents for the polar capsules or sprays there may be used lowmolecular weight polyethyleneglycols (PEG) of 400-1000 Mw (preferably400-600), low molecular weight (C₂-C₈) mono and polyols and alcohols ofC₇-C₁₈ linear or branch chain hydrocarbons, glycerin may also be presentand water may also be used in the sprays, but only in limited amount inthe capsules.

It is expected that some glycerin and water used to make the gelatinshell will migrate from the shell to the fill during the curing of theshell. Likewise, there may be some migration of components from the fillto the shell during curing and even throughout the shelf-life of thecapsule. Therefore, the values given herein are for the compositions asprepared, it being within the scope of the invention that minorvariations will occur.

The preferred flavoring agents are synthetic or natural oil ofpepper-mint, oil of spearmint, citrus oil, fruit flavors, sweeteners(sugars, aspartame, saccharin, etc.), and combinations thereof.

The active substances include the active compounds selected from thegroup consisting of cyclosporine, sermorelin, Octreotide acetate,cal-citonin-salmon, insulin lispro, sumatriptan succinate, clozapine,cyclo-benzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine,erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydrinate,cimetidine hydrochloride, famotidine, phenytoin sodium, phenytoin,carboprost thromethamine, carboprost, diphenhydramine hydrochloride,isoproterenol hydrochloride, terbutaline sulfate, terbutaline,theophylline, albuterol sulfate and neutraceuticals, that is to saynutrients with pharmacological action such as but not limited tocarnitine, valerian, echinacea, and the like.

The formulations of the present invention comprise an active compound ora pharmaceutically acceptable salt thereof. The term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic acids or bases including organic and inorganicacids or bases.

When an active compound of the present invention is acidic, salts may beprepared from pharmaceutically acceptable non-toxic bases. Salts derivedfrom all stable forms of inorganic bases include aluminum, ammonium,calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium,zinc, etc. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion-exchange resins such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethyl-aminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl-piperidine,glucamine, glucosamine, histidine, isopropylamine, lysine,methyl-glucosamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purine, theobromine, triethylamine, trimethylamine,tripropylamine, etc.

When an active compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric,pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, etc. Particularly preferred are citric, hydrobromic,maleic, phosphoric, sulfuric, and tartaric acids.

In the discussion of methods of treatment herein, reference to theactive compounds is meant to also include the pharmaceuticallyacceptable salts thereof. While certain formulations are set forthherein, the actual amounts to be administered to the mammal or man inneed of same are to be determined by the treating physician.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting.

The following are examples of each class (all values unless otherwisespecified are in weight percent):

EXAMPLE 1 Biologically Active Peptides Including Peptide Hormones

A. Cyclosporine lingual spray most preferred Amounts preferred amountamount Cyclosporine 5-50 10-35 15-25 water 5-20 7.5-50  9.5-12  ethanol5-60 7.5-50  10-20 polyethylene glycol 20-60  30-45 35-40 flavors0.1-5   1-4 2-3 

B. Cyclosporine Non-Polar lingual spray most preferred Amounts preferredamount amount Cyclosporine 1-50 3-40  5-30 Migylol ®* 30-40Polyoxyethylated 30-40 castor oil Butane 25-80  30-70  33-50 flavors0.1-5   1-4  2-3 *Miglyol is a registered trademark of Huels AG anddescribes a fractionated coconut oil of boiling point 240-270° C.comprising saturated C₈ and C₁₀ triglycerides. 

C. Cyclosporine non-polar bite capsule most preferred Amounts preferredamount amount Cyclosporine  1-35 5-25 10-20 olive oil 25-60 35-55  30-45polyoxyethyl- 25-60 35-55  30-45 ated oleic glycerides flavors 0.1-5  1-4  2-3 

D. Cyclosporine bite capsule most preferred Amounts preferred amountamount Cyclosporine 5-50 10-35 15-25 polyethylene glycol 20-60  30-4535-40 glycerin 5-30 7.5-25  10-20 propylene glycol 5-30 7.5-25  10-20flavors 0.1-10   1-8 3-6 

E. Sermorelin (as the acetate) lingual spray Amounts preferred amountmost preferred sermorelin (as the .01-5 .1-3   .2-1.0 acetate) mannitol,  1-25  5-20 10-15 monobasic sodium 0.1-5 1-3 1.5-2.5 phosphate, dibasicsodium 0.01-5  .05-3   0.1-0.5 phosphate water ethanol   5-30 7.5-25 9.5-15  polyethylene glycol   20-60 30-45 35-40 propylene glycol   5-2510-20 12-17 flavors 0.1-5 1-4 2-3 

F. Octreotide acetate (Sandostatin*) lingual spray most preferredAmounts preferred amount amount octreotide acetate 0.001-0.5  0.005-0.250 0.01-0.10 acetic acid 1-10 2-8 4-6 sodium acetate 1-10 2-84-6 sodium chloride 3-30  .5-25  15-20 flavors 0.1-5   0.5-.4  2-3ethanol 5-30 7.5-20  9.5-15  water 15-95  35-90 65-85 flavors 0.1-5  1-4 2-3 

G. Calcitonin-salmon lingual spray most preferred Amounts preferredamount amount Calcitonin-salmon 0.001-5    0.005-2    01-1.5 ethanol2-15 3-10  7-9.5 water 30-95  50-90  60-80  polyethylene glycol 2-153-10  7-9.5 sodium chloride 2.5-20   5-15  10-12.5 flavors 0.1-5   1-4 2-3  

H. insulin lispro, lingual spray most preferred Amounts preferred amountamount insulin, 20-60    4-55 5-50 glycerin, 0.1-10   0.25-5  0.1-1.5 dibasic sodium 1-15 2.5-10 4-8  phosphate, m-cresol, 1-25   5-257.5-12.5 zinc oxide 0.01-0.25    .05-0.15 0.075-0.10  m-cresol, 0.1-1   0.2-0.8 0.4-0.6  phenol trace amounts trace amounts trace amountsethanol 5-20 7.5-15 9-12 water 30-90   40-80 50-75  propylene glycol5-20 7.5-15 9-12 flavors 0.1-5   0.5-3  0.75-2    adjust pH to 7.0-7.8with HCl or NaOH 

EXAMPLE 2 CNS Active Amines and their Salts: Including but not Limitedto Tricyclic Amines, GABA Analogues, Thiazides, PhenothiazineDerivatives, Serotonin Antagonists and Serotonin Reuptake Inhibitors

A. Sumatriptan succinate lingual spray most preferred Amounts preferredamount amount sumatriptan succinate 0.5-30     1-20 10-15 ethanol 5-607.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 5-30 7.5-20 10-15 flavors 0.1-5    1-4 2-3 

B. Sumatriptan succinate bite capsule most preferred Amounts preferredamount amount sumatriptan succinate 0.01-5   0.05-3.5  0.075-1.75 polyethylene glycol 25-70 30-60 35-50 glycerin 25-70 30-60 35-50 flavors0.1-10  1-8 3-6 

C. Clozepine lingual spray most preferred Amounts preferred amountamount Clozepine 0.5-30     1-20 10-15 ethanol 5-60 7.5-50 10-20propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60  30-45 35-40water 5-30 7.5-20 10-15 flavors 0.1-5    1-4 2-3 

D. Clozepine Non-Polar lingual spray with propellent most preferredAmounts preferred amount amount Clozepine 0.5-30 1-20 10-15 Migylol 20-85 25-70  30-40 Butane  15-80 30-75  60-70 flavors 0.1-5  1-4  2-3 

E. Clozepine Non-Polar lingual spray without propellant most preferredAmounts preferred amount amount Clozepine 0.5-30 1-20 10-15 Migylol   70-99.5  80-99  85-90 flavors 0.1-5  1-4  2-3 

F. Cyclobenzaprine Non polar lingual spray most preferred Amountspreferred amount amount Cyclobenzaprine 0.5-30 1-20 10-15 (base) Migylol 20-85 25-70  30-40 Iso-butane  15-80 30-75  60-70 flavors 0.1-5  1-4 2-3 

G. dexfenfluramine hydrochloride lingual spray preferred most preferredAmounts amount amount dexfenfluramine Hcl 5-30 7.5-20 10-15 ethanol 5-607.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 5-30 7.5-20 10-15 flavors 0.1-5    1-4 2-3 

EXAMPLE 3 Sulfonylureas

A. Glyburide lingual spray most preferred Amounts preferred amountamount Glyburide 0.25-25   0.5-20 0.75-15   ethanol 5-60 7.5-50 10-20propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60  30-45 35-40water 2.5-30     5-20  6-15 flavors 0.1-5    1-4 2-3 

B. Glyburide non-polar bite capsule most preferred Amounts preferredamount amount Glyburide 0.01-10   0.025-7.5  0.1-4  olive oil 30-6035-55  30-50 polyoxyethyl- 30-60 35-55  30-50 ated oleic glyceridesflavors 0.1-5   1-4  2-3 

EXAMPLE 4 Antibiotics Anti-Fungals and Anti-Virals

A. zidovudine [formerly called azidothymidine (AZT) (Retrovir) non-polarlingual spray most preferred Amounts preferred amount amount zidovudine10-50 15-40 25-35 Soya oil 20-85 25-70 30-40 Butane 15-80 30-75 60-70flavors 0.1-5   1-4 2-3 

B. Erythromycin bite capsule bite capsule most preferred Amountspreferred amount amount Erythromycin 25-65  30-50 35-45 polyoxyethyleneglycol 5-70 30-60 45-55 glycerin 5-20 7.5-15    10-12.5 flavors 1-10 2-83-6 

C. Ciprofloxacin hydrochloride bite capsule most preferred Amountspreferred amount amount Ciprofloxacin 25-65 35-55 40-50 hydrochlorideglycerin  5-20 7.5-15    10-12.5 polyethylene glycol 20-75 30-65 40-60flavors  1-10 2-8 3-6 

D. zidovudine [formerly called azidothymidine (AZT) (Retrovir) lingualspray most preferred Amounts preferred amount amount zidovudine 10-5015-40 25-35 water 30-80 40-75 45-70 ethanol  5-20 7.5-15   9.5-12.5polyethylene glycol  5-20 7.5-15   9.5-12.5 flavors 0.1-5   1-4 2-3 

EXAMPLE 5 Anti-Emetics

A. Ondansetron hydrochloride lingual spray most preferred Amountspreferred amount amount ondansetron hydro- 1-25 2-20 2.5-15 chloridecitric acid mono- 1-10 2-8  2.5-5  hydrate, sodium citrate di- 0.5-5  1-4   1.25-2.5  hydrate water 1-90 5-85  10-75 ethanol 5-30 7.5-20  9.5-15 propylene glycol 5-30 7.5-20   9.5-15 polyethylene glycol 5-307.5-20   9.5-15 flavors 1-10 3-8     5-7.5  

B. Dimenhydrinate bite capsule most preferred Amounts preferred amountamount Dimenhydrinate 0.5-30   2-25 3-15 glycerin 5-20 7.5-15    10-12.5polyethylene glycol 45-95  50-90  55-85  flavors 1-10 2-8  3-6  

C. Dimenhydrinate polar lingual spray most preferred Amounts preferredamount amount Dimenhydrinate 3-50 4-40 5-35 water 5-90 10-80  15-75 ethanol 1-80 3-50 5-10 polyethylene 1-80 3-50 5-15 glycol Sorbitol0.1-5   0.2-4   0.4-1.0  aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors0.1-5   1-4  2-3  

EXAMPLE 6 Histamine H-2 Receptor Antagonists

A. Cimetidine hydrochloride bite capsule most preferred Amountspreferred amount amount Cimetidine Hcl 10-60 15-55 25-50 glycerin  5-207.5-15    10-12.5 polyethylene 20-90 25-85 30-75 glycol flavors  1-102-8 3-6 

B. Famotidine lingual spray most preferred Amounts preferred amountamount Famotidine   1-35 5-30 7-20 water 2.5-25 3-20 5-10 L-asparticacid 0.1-20 1-15 5-10 polyethylene glycol  20-97 30-95  50-85  flavors0.1-10  1-7.5 2-5  

C. Famotidine non-polar lingual spray most preferred Amounts preferredamount amount Famotidine  1-35  5-30  7-20 Soya oil 10-50 15-40 15-20Butane 15-80 30-75 45-70 polyoxyethyl- 10-50 15-40 15-20 ated oleicglycerides flavors 0.1-5   1-4 2-3 

EXAMPLE 7 Barbiturates

A. Phenytoin sodium lingual spray most preferred Amounts preferredamount amount Phenytoin sodium 10-60   15-55  20-40 water 2.5-25    3-20   5-10 ethanol 5-30 7.5-20 9.5-15 propylene glycol 5-30 7.5-209.5-15 polyethylene glycol 5-30 7.5-20 9.5-15 flavors 1-10  3-8   5-7.5  

B. Phenytoin non-polar lingual spray most preferred Amounts preferredamount amount Phenytoin  5-45 10-40 15-35 migylol 10-50 15-40 15-20Butane 15-80 30-75 60-70 polyoxyethyl- 10-50 15-40 15-20 ated oleicglycerides flavors 0.1-10  1-8   5-7.5 

EXAMPLE 8 Prostaglandins

A. Carboprost thromethamine lingual spray most preferred Amountspreferred amount amount Carboprost thrometha- 0.05-5    0.1-3  0.25-2.5 mine water 50-95   60-80 65-75  ethanol 5-20 7.5-15 9.5-12.5polyethylene glycol 5-20 7.5-15 9.5-12.5 sodium chloride 1-20   3-154-8  flavors 0.1-5    1-4 2-3  pH is adjusted with sodium hydroxideand/or hydrochloric acid 

B. Carboprost non-polar lingual spray most preferred Amounts preferredamount amount Carboprost 0.05-5   0.1-3   0.25-2.5  migylol 25-50 30-4535-40 Butane  5-60 10-50 20-35 polyoxyethyl- 25-50 30-45 35-40 atedoleic glycerides flavors 0.1-10  1-8   5-7.5 

EXAMPLE 9 Neutraceuticals

A. Carnitine as bite capsule (contents are a paste) most preferredAmounts preferred amount amount Carnitine fumarate 6-80 30-70   45-65soya oil 7.5-50   10-40 12.5-35 soya lecithin 0.001-1.0   0.005-0.5   .01-0.1 Soya fats 7.5-50   10-40 12.5-35 flavors 1-10 2-8   3-6 

B. Valerian as lingual spray most preferred Amounts preferred amountamount Valerian extract 0.1-10   0.2-7  0.25-5  water 50-95   60-80  65-75 ethanol 5-20 7.5-15   9.5-12.5 polyethylene glycol 5-20 7.5-15  9.5-12.5 flavors 1-10  2-8   3-6 

B. Echinacea as bite capsule most preferred Amounts preferred amountamount Echinacea extract  30-85 40-75   45-55 soya oil 7.5-50 10-4012.5-35 soya lecithin 0.001-1.0    0.005-0.5    .01-0.1 Soya fats 7.5-5010-40 12.5-35 flavors   1-10 2-8   3-6 

B. Mixtures of ingredients most preferred Amounts preferred amountamount Magnesium oxide 15-40   20-35   25-30 Chromium picolinate0.01-1.0   0.02-0.5   .025-0.75 folic acid .025-3.0   0.05-2.0  0.25-0.5vitamin B-12 0.01-1.0   0.02-0.5   .025-0.75 vitamin E 15-40   20-35  25-30 Soya oil 10-40 12.5-35   15-20 soya lecithin 0.1-5   0.2-4  0.5-1.5 soya fat 10-40   15-35 17.5-20 

EXAMPLE 10 Sleep Inducers (Also CNS Active Amine)

A. Diphenhydramine hydrochloride lingual spray most preferred Amountspreferred amount amount Diphenhydramine 3-50 4-40 5-35 Hcl water 5-9010-80  50-75  ethanol 1-80 3-50 5-10 polyethylene 1-80 3-50 5-15 glycolSorbitol 0.1-5   0.2-4   0.4-1.0  aspartame 0.01-0.5  0.02-0.4 0.04-0.1  flavors 0.1-5   1-4  2-3  

EXAMPLE 11 Anti-Asthmatics-Bronchodilators

A. Isoproterenol Hydrochloride as polar lingual spray most preferredAmounts preferred amount amount Isoproterenol 0.1-10 0.2-7.5  0.5-6  Hydrochloride water   5-90 10-80  50-75  ethanol   1-80 3-50 5-10polyethylene   1-80 3-50 5-15 glycol Sorbitol 0.1-5  0.2-4   0.4-1.0 aspartame  0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5  1-4  2-3  

B. Terbutaline sulfate as polar lingual spray most preferred Amountspreferred amount amount Terbutaline 0.1-10   0.2-7.5 0.5-6 sulfate water  5-90   10-80   50-75 ethanol   1-10   2-8 2.5-5 Sorbitol 0.1-5  0.2-4  0.4-1.0 aspartame  0.01-0.5   0.02-0.4  0.04-0.1 flavors 0.1-5    1-4  2-3 

C. Terbutaline as non-polar lingual spray most preferred Amountspreferred amount amount Terbutaline 0.1-10 0.2-7.5 0.5-6   migylol 25-50 30-45 35-40 isobutane   5-60 10-50 20-35 polyoxyethylated  25-5030-45 35-40 oleic glycerides flavors 0.1-10 1-8   5-7.5 

D. Theophylline polar bite capsule most preferred Amounts preferredamount amount Theophylline  5-50 10-40 15-30 polyethylene 20-60 25-5030-40 glycol glycerin 25-50 35-45 30-40 propylene glycol 25-50 35-4530-40 flavors 0.1-5   1-4 2-3 

E. Albuterol sulfate as polar lingual spray most preferred Amountspreferred amount amount Albuterol sulfate 0.1-10   0.2-7.5 0.5-6 water  5-90   10-80   50-75 ethanol   1-10   2-8 2.5-5 Sorbitol 0.1-5  0.2-4  0.4-1.0 aspartame  0.01-0.5   0.02-0.4  0.04-0.1 flavors 0.1-5    1-4  2-3 

EXAMPLE 12 Polar Solvent Formulations Using a Propellant

A. Sulfonylurea Most-Preferred Amount Preferred Amount Amount Glyburide 0.1-25%  0.5-15% 0.6-10% Ethanol   40-99%   60-97%  70-97% Water0.01-5%  0.1-4% 0.2-2%  Flavors 0.05-10% 0.1-5%  0.1-2.5% Propellant  2-10%   3-5%  3-4% 

B. Prostaglandin E₁ (vasodilator) Most-Preferred Amount Preferred AmountAmount Prostaglandin E₁ 0.01-10% 0.1-5% 0.2-3% Ethanol   10-90%   20-75%  25-50% Propylene glycol   1-90%   5-80%   10-75% Water 0.01-5%  0.1-4%0.2-2% Flavors 0.05-10% 0.1-5%   0.1-2.5% Propellant   2-10%   3-5%  3-4% 

C. Promethazine (antiemetic, sleep inducer, and CNS active amine)Most-Preferred Amount Preferred Amount Amount Promethazine 1-25% 3-15%5-12% Ethanol 10-90%  20-75%  25-50%  Propylene glycol 1-90% 5-80%10-75%  Water 0.01-5%    0.1-4%   0.2-2%   Flavors 0.05-10%   0.1-5%  0.1-2.5%  Propellant 2-10% 3-5%  3-4%  

D. Meclizine Most-Preferred Amount Preferred Amount Amount Meclizine1-25% 3-15% 5-12% Ethanol 1-15% 2-10% 3-6    Propylene glycol 20-98% 5-90% 10-85%  Water 0.01-5%    0.1-4%   0.2-2%   Flavors 0.05-10%  0.1-5%   0.1-2.5%  Propellant 2-10% 3-5%  3-4%  

1. A method for administering an effective amount of a pharmacologicallyactive compound to a mammal to provide transmucosal absorption of apharmacologically effective amount of the active compound through theoral mucosa of the mammal to the systemic circulatory system of themammal, comprising: spraying the oral mucosa of the mammal with a buccalspray composition, containing a pharmacologically active compounddissolved in a pharmacologically acceptable solvent, comprising in weighpercent of the composition: an active compound in an amount of between0.1 and 25 percent selected from the group consisting of a biologicallyactive peptide, central nervous system active amine, sulfonyl urea,antibiotic, antifungal, sleep inducer, antiasthmatic, antiemetic,antiviral, histamine H-2 receptor antagonist, barbiturate,prostaglandin, or bronchial dilator; a polar solvent in an amountbetween 10 and 97 percent; and a propellant in an amount between 2 and10 percent, wherein said propellant is a C₃ to C₅ hydrocarbon of linearor branched configuration.
 2. The method of claim 1, wherein the spraycomposition further comprises flavoring a agent in an amount between0.05 and 10 percent by weight of the total composition.
 3. The method ofclaim 2, wherein the polar solvent is present in an amount between 20and 97 percent by weight of the total composition, the active compoundis presented in an amount between 0.1 and 15 percent by weight of thetotal composition, the propellant is presented in an amount between 2and 10 percent by weight of the composition, and the flavoring agent ispresent in an amount between 0.1 and 5 percent by weight of the totalcomposition.
 4. The method of claim 3, wherein the polar solvent ispresent in an amount between 25 and 97 percent by weight of the totalcomposition, the active compound is present in an amount between 0.2 and25 percent by weight of the total composition, the propellant is presentin an amount between 2 and 10 percent by weight of the composition, andthe flavoring agent is present in an amount between 0.1 and 2.5 percentby weight of the total composition.
 5. The method of claim 1, whereinthe polar solvent comprises a polyethyleneglycol having a molecularweight between 400 and 1000 g/mol, C₂ to C₈ mono- and poly-alcohol or C₇to C₁₈ alcohol of linear or branched configuration.
 6. The method ofclaim 1, wherein the polar solvent comprises aqueous polyethyleneglycol.
 7. The method of claim 1, wherein the polar solvent comprisesaqueous ethanol.
 8. The method of claim 1, wherein the active compoundis selected from the group consisting of cyclosporine, clozapine,zidevudine, erythromycin, ondansetron, cimetidine, phenytoin, carboprostthromethamine, valerian, or a pharmaceutically acceptable salt thereof.9. The method of claim 1, wherein the flavoring agent comprises asynthetic or natural oil of peppermint, oil of spearmint, citrus oil,fruit flavor, sweetener or mixture thereof.
 10. The method of claim 1,wherein the polar solvent is present in an amount between 55 and 72percent by weight of the total composition, the active compound iscyclosporine present in an amount between 15 and 25 percent by weight ofthe total composition, the propellant is present in an amount between 2and 10 percent by weight of the composition, and the flavoring agent ispresent in an amount between 0.1 and 5 percent by weight of the totalcomposition.
 11. The method of claim 1, wherein the polar solvent ispresent in an amount between 19 and 90 percent by weight of the totalcomposition, the active compound is ondansetron hycrochloride present inan amount between 2.5 and 15 percent by weight of the total composition,the propellant is present in an amount between 2 and 10 percent byweight of the composition, and the flavoring agent is present in anamount between 1 and 10 percent by weight of the total composition. 12.The method of claim 1, wherein the propellant comprises propane,N-butane, iso-butane, N-pentane, iso-pentane, neo-pentane, or a mixturethereof.
 13. A method for administering an effective amount of apharmacologically active compound to a mammal to provide transmucosalabsorption of a pharmacologically effective amount of the activecompound through the oral mucosa of the mammal to the systemiccirculatory system of the mammal, comprising: spraying the oral mucosaof the mammal with a buccal spray composition, containing apharmacologically active compound dissolved in a pharmacologicallyacceptable solvent, comprising in weight percent of the composition: anactive compound in an amount between 0.1 and 25 percent selected fromthe group consisting of an antihistamine, alkaloid, hormone,benzodiazepine or analgesic; a polar solvent in an amount between 10 and97 percent; and a propellant in an amount between 2 and 10 percent,wherein said propellant is a C₃ to C₈ hydrocarbon of linear or branchedconfiguration.